Tumor necrosis factor (TNF) is the prototypic member of a family of cytokines, which interact with their receptors to carry out diverse functions. Some TNF-receptor family members, termed the “death receptors”, possess an intracellular “death domain”, and have the unique ability to transmit an intracellular death signal. TRAIL (Tumor necrosis factor related apoptosis inducing ligand), also known as Apo2L, was originally identified through its homology to TNF, FasL, and other members of the TNF superfamily. Addition of TRAIL induces apoptosis of many tumor cell lines but interestingly, has no apoptotic effect on most normal non-transformed cells. In humans, four members of the TNF receptor superfamily can bind TRAIL: TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1, TRID), and TRAIL-R4 (DcR2, TRUNDD).
TRAIL-R1 (DR4) and -R2 (DR5) possess an intracellular tail containing a conserved motif known as the death domain. As in TNF-RI and Fas, this domain allows interaction with the downstream adapter protein(s) to initiate apoptotic signals. In contrast, TRAIL-R3 possesses a truncated cytoplasmic tail lacking a death domain and TRAIL-R4 exists as a GPI-linked protein. These latter two receptors are thought to function as decoy proteins that can inhibit signaling through TRAIL-R1 and -R2. The fifth receptor for TRAIL, osteoprotegerin, is a soluble protein that participates in regulation of bone density. Osteoprotegerin can inhibit TRAIL-mediated apoptosis in vitro but its functional relationship with TRAIL in vivo is not clear. In mice, there is only one full-length receptor, TRAIL-R (mDR4/5, mTRAILR2, mKILLER), which is equally homologous to human DR4 and DR5. Like its human homologues, this receptor is capable of signaling apoptosis following either over-expression or receptor ligation by TRAIL. Two murine decoy receptors (mDcTRAILR1 and mDcTRAILR2) have also been recently reported. They lack a death domain and do not induce apoptosis in sensitive cells.
The ability to preferentially signal apoptosis in transformed cells has led to numerous studies of the mechanism of TRAIL-R signaling. TRAIL-R can induce apoptosis in a FADD dependent manner. Similar to Fas, only FADD and caspase-8 were found in the TRAIL-R signaling complex in some studies. In contrast, others have reported the recruitment of TRADD and RIP to the signaling complex and showed that TRAIL-R, like TNF-R, can activate NF-κB and JNK. These discrepancies could be due to differences in cell lines or cell type-specific signaling. However, the similarity to TNF receptor signaling has led to speculation that sensitivity to TRAIL induced apoptosis may be regulated by expression of anti-apoptotic factors downstream of NF-κB or by more proximal factors such as c-FLIP, which inhibits caspase-8 activation. In addition, mitochondrial factors such as SMAC/Diablo have been implicated in regulating TRAIL-R induced apoptosis. Indeed, it may be a combination of different cytoplasmic factors, which regulate sensitivity to TRAIL-R induced apoptosis.
While the ability to induce apoptosis in transformed cells is well established, the role of TRAIL and its receptor(s) in normal mammalian physiology is not understood. TRAIL has been shown to be expressed on the surface of Natural Killer (NK) and T cells, macrophages and dendritic cells in an activation dependent manner; however, its function remains unclear. Cells normally resistant to TRAIL induced apoptosis can become sensitive following viral infection, and treatment of mice with neutralizing anti-TRAIL antibodies enhances their sensitivity to encephalomyocarditis virus (EMCV). TRAIL-deficient animals display increased susceptibility to tumor metastasis and autoimmune disease progression as well as defects in negative selection, although this latter finding is controversial. These data suggest that TRAIL may play roles in tumor surveillance, regulation of autoimmunity, and T cell development.
Relevant Literature
A review of the TNF receptor superfamily may be found in Baker and Reddy (1998) Oncogene 17(25):3261-70. The tumor necrosis factor receptor (TNF-R) superfamily represents a growing family, with over 20 members having been identified thus far in mammalian cells. These proteins share significant homology in their extracellular ligand binding domains and intracellular effector (death) domains. Death signals seem to be associated with the activation of the caspase pathway. In addition to cell death, some members of this family, especially TNF-R, can signal activation of transcription factors (such as Jun and NF-κB) and inflammatory responses. Gravestein and Borst (1998) Semin Immunol 10(6):423-34 also review this receptor superfamily. The use of TRAIL as an anti-tumor agent is discussed in Walczak et al. (1999) Nature Medicine 5:157-163.